I. Influence of sex and age on alcohol metabolism and responses Previous research indicates that alcohol metabolism differs between men and women, and may also be influenced by age. There appears to be a complex interaction between sex, age and alcohol metabolism, and differences in sex steroidal hormones, estrogen and testosterone, may underlie this interaction. Studies have also shown sex- and age-related differences in alcohol pharmacodynamics, although the underlying determinants of these differences are unclear. The objective of this study was to evaluate the influence of sex and age on the metabolism and acute response to alcohol in social drinkers. This was a randomized, two-session crossover study in 48 male and female - 24 young (21-25 years) and 24 older (55-65 years) - social drinkers. Participants underwent the alcohol clamp at target BrACs of 0 and 50 mg% for 3 hrs. The alcohol elimination rate (AER) and behavioral and physiological responses to alcohol were evaluated. Analysis of the pharmacokinetic data indicates that AERs are significantly higher in males than in females, as expected. AER/LBM was similar between males and females, indicating that sex differences in LBM may contribute to the observed sex differences in AER. Age did not appear to influence AER. AER/LBM was higher in older compared to younger subjects. LBM was significantly associated with AER (r2=0.42) across subjects. LV was also significantly associated with AER (r2=0.23) across subjects. Analysis of the PD data showed a significant effect of alcohol on peak subjective perceptions of high, intoxication and drug effects. There were no sex differences in subjective responses to clamped BrACs. Older subjects reported similar peak ratings of high and intoxicated as younger subjects. However, they showed significantly lower peak ratings for liking drug effects and wanting more than younger subjects. These results are being written up for publication. Preliminary analysis of the hormonal data indicates a lack of relationship between baseline levels of GH, IGF1, and sex steroid levels on AER. Analysis of the effect of alcohol on GH, IGF-1 and sex steroid levels revealed a complex pattern of responses that appeared to differ by sex and age. Change in free testosterone levels showed a significant treatment X baseline interaction, suggesting that the alcohol-induced decrease in testosterone levels was seen primarily in males. Change in estradiol levels showed a main effect of treatment with alcohol and a significant treatment X baseline interaction as well as a significant treatment X sex interaction, indicating that alcohol resulted in an increase in estradiol in females and a decrease in estradiol in males, compared to placebo. Change in IGF1 levels did not show a main effect of treatment, however it demonstrated a main effect of baseline and a trend for treatment X age interaction. Change in GH showed a main effect of baseline and main effect of sex, and a trend for treatment X baseline interaction, suggesting that males showed greater increases in GH levels across treatment compared to females. These results are also being written up for publication. Additional analyses, including PK-PD modeling are being conducted to evaluate the influence of age and sex on subjective responses and heart rate changes during the alcohol clamp. Findings from these studies will provide a better understanding of age- and sex-related differences in alcohol metabolism, which may underlie medically important differences in individual responses to alcohol. II. Computer-assisted self-infusion of ethanol (CASE) in humans Self-administration is a well-established characteristic of addictive drugs. The usual method of studying human alcohol self-administration is by assessing the ingestion of alcoholic beverages, typically in a laboratory setting. However, these methods remain imprecise and may be unreliable because they are subject to substantial variability in alcohol exposures due to differences in the definition of standardized drinks and drinking schedules as well as the high inter-individual PK variability. Also, alcohol exposure cannot be controlled once alcohol is ingested, and these methods are subject to various non-pharmacological influences such as alcohol expectancy, beverage preference, choice and monetary value of incentives or disincentives for drinking. A computer-assisted method of alcohol self-administration, using the PBPK-model based infusion algorithm, provides subjects with the flexibility to choose when to push a button to receive alcohol, while providing the investigator with flexibility in controlling the subsequent time course of breath (and therefore brain) alcohol exposure, assuring the same increments across all participants, and preventing the BrAC from exceeding any pre-set upper limit. Thus, the CASE method minimizes PK variability, and focuses on assessment of behavior driven by the pharmacological effects of the drug. The purpose of this study is to characterize the CASE paradigm by assessing self-administration behavior and the resulting BrAC exposure and pharmacodynamic responses in healthy social drinkers. During the CASE session, subjects first undergo a directed priming phase, where they are prompted to push a button to receive standardized alcohol infusions. This is followed by an ad-lib phase, where they have free access to the standardized alcohol infusions. BrAC is measured serially, and physiological and subjective measures of alcohol effects and urges are assessed. Primary self-administration measures include number of button presses (NBP), average BrAC (AVG) and peak BrAC (PEAK). Analysis of the test-retest data indicated a high degree of correlation between self-administration measures across sessions. Correlations between measures within each session demonstrated a high level of internal consistency. Preliminary analysis indicated a significant association between recent drinking history measures and self-administration measures. There did not appear to be any sex differences in self-administration measures. Subjective measures of craving following the priming phase were significantly associated with self-administration measures. There was a strong association between peak alcohol effects of feeling drug effects, liking drug effects, intoxication, stimulation and self-administration measures. Data collection for this study is expected to be completed soon. The next step is the development of an operant paradigm, using a progressive ratio schedule to evaluate alcohol self-administration using the CASE system. The Section is also conducting studies using the CASE method to examine the effects of pharmacological agents on the rate, magnitude and pattern of exposure to alcohol in heavy drinkers. Such a paradigm could serve as a biomarker of clinical efficacy in the early stages of development of drugs for the treatment of alcohol-dependence. The first of these studies was initiated last year. This randomized, double-blind placebo-controlled study aims to evaluate the effect of varenicline on alcohol self-administration using the CASE method in non-treatment seeking heavy drinkers. III. Additional Studies: 1) Effect of mu-opioid receptor gene (A118G) polymorphism on the response to alcohol, including dopamine release (using 11C-raclopride displacement), in healthy social drinkers (Markus Heilig, P.I.). This study has been completed and the paper published (Ramchandani et al., 2010). 2) Effect of alcohol on BOLD response using fMRI in healthy social and heavy drinkers (Daniel Hommer, P.I.). Study is ongoing. 3) Effect of naltrexone on the BOLD signal in the ventral striatum during the alcohol clamp in alcohol-dependent individuals (David T. George, PI). Study is ongoing.